tbuckley/cabot-search huggingface dataset:
ATRT-12. LIN28A expression correlates with poor prognosis and the MYC subgroup in AT/RTs
Authors: Matthias Dottermusch, Sina Brakopp, Nina Struve, Michael C Frühwald, Daniel J Merk, Ghazaleh Tabatabai, Ulrich Schüller, Martin Hasselblatt, Julia E Neumann
Journal: Neuro-Oncology (2022)

Abstract Atypical teratoid/rhabdoid tumors (AT/RTs) are malignant embryonal tumors of the central nervous system, which mainly affect young children. These tumors are defined by loss of SMARCB1 (or SMARCA4 in rare cases) and can be categorized into three main DNA methylation subgroups (i.e. –MYC, -SHH, -TYR). AT/RTs commonly display heterogeneous expression of LIN28A, an RNA-binding protein, which regulates pluripotency and plays critical roles during embryonic development. The biological impact and clinical significance of LIN28A expression in AT/RTs remains unknown. In this study, we investigated 80 samples of molecularly and clinically characterized AT/RTs for LIN28A expression using immunohistochemistry. Staining signal of tumor tissue was assessed and scored via semi-automated digital image analysis. Global LIN28A expression intensity and heterogeneity were tested for correlation with DNA methylation subtype, tumor localization, as well as patient age, gender and overall survival. LIN28A was found with strongly varying staining patterns and intensities across our cohort of AT/RTs, with significantly elevated expression in the MYC subgroup. Moreover, we identified strong global and focal LIN28A expression as an independent negative prognostic factor in AT/RTs. In summary, we show that AT/RT-MYC tumors display significantly increased LIN28A expression in comparison to the other DNA methylation subgroups, suggesting a subgroup-specific intratumoral role of LIN28A. Furthermore, we demonstrate an impact of LIN28A expression on survival in AT/RTs. Further investigations on the functions of LIN28A in AT/RTs in vitro and in vivo are ongoing and aim to uncover potential therapeutic implications in these tumors.
Association of Uric Acid–Lowering Therapy With Incident Chronic Kidney Disease
Authors: Waleed Hassan, Prabin Shrestha, Keiichi Sumida, Fridtjof Thomas, Patrick L. Sweeney, Praveen K. Potukuchi, Connie M. Rhee, Elani Streja, Kamyar Kalantar-Zadeh, Csaba P. Kovesdy
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Uric acid is a waste metabolite produced from the breakdown of purines, and elevated serum uric acid levels are associated with higher risk of hypertension, cardiovascular disease, and mortality and progression of chronic kidney disease (CKD). Treatment of hyperuricemia in patients with preexisting CKD has not been shown to improve kidney outcomes, but the associations of uric acid–lowering therapies with the development of new-onset kidney disease in patients with estimated glomerular filtration rate (eGFR) within reference range and no albuminuria is unclear. <h3>Objective</h3> To examine the association of initiating uric acid–lowering therapy with the incidence of CKD. <h3>Design, Setting, and Participants</h3> This cohort study included patients with eGFR of 60 mL/min/1.73 m<sup>2</sup>or greater and no albuminuria treated at US Department of Veterans Affairs health care facilities from 2004 to 2019. Clinical trial emulation methods, including propensity score weighting, were used to minimize confounding. Data were analyzed from 2020 to 2022. <h3>Exposure</h3> Newly started uric acid–lowering therapy. <h3>Main Outcomes and Measures</h3> The main outcomes were incidences of eGFR less than 60 mL/min/1.73 m<sup>2</sup>, new-onset albuminuria, and end-stage kidney disease. <h3>Results</h3> A total of 269 651 patients were assessed (mean [SD] age, 57.4 [12.5] years; 252 171 [94%] men). Among these, 29 501 patients (10.9%) started uric acid–lowering therapy, and 240 150 patients (89.1%) did not. Baseline characteristics, including serum uric acid level, were similar among treated and untreated patients after propensity score weighting. In the overall cohort, uric acid–lowering therapy was associated with higher risk of both incident eGFR less than 60 mL/min/1.73 m<sup>2</sup>(weighted subhazard ratio [SHR], 1.15 [95% CI, 1.10-1.20;<i>P</i> &lt; .001) and incident albuminuria (SHR, 1.05 [95% CI, 1.01-1.09;<i>P</i> &lt; .001) but was not associated with the risk of end-stage kidney disease (SHR, 0.96 [95% CI, 0.62-1.50];<i>P</i> = .87). In subgroup analyses, the association of uric acid–lowering therapy with worse kidney outcomes was limited to patients with baseline serum uric acid levels of 8 mg/dL or less. <h3>Conclusions and Relevance</h3> These findings suggest that in patients with kidney function within reference range, uric acid–lowering therapy was not associated with beneficial kidney outcomes and may be associated with potential harm in patients with less severely elevated serum uric acid levels.
Tissue-based next generation sequencing (NGS) testing in solid tumors: A single-center experience in Malaysia.
Authors: Azura Rozila Ahmad, Yi Long Toh, William Tan, Mohamed Ibrahim A. Wahid
Journal: Journal of Clinical Oncology (2022)

e15121 Background: There is an increased appreciation for precision oncology in which clinicians are utilizing NGS testing to guide treatment selection and to identify resistance mutations. This study aims to identify clinically significant biomarkers in prospectively collected FFPE tumor tissue specimens. Genomic testing of molecular alterations was conducted using an in-house 50-gene hotspot APEX panel (MiRXES). Herein, we report a single center experience with targeted NGS panel testing in solid tumors. Methods: The analyzed cohort consisted of 75 clinical samples submitted for molecular testing over a 3-month period from Beacon Hospital, Malaysia (October to December 2021). The identified variants were tiered according to AMP/ASCO/CAP guidelines, in which actionable targets are defined as being able to be matched with existing FDA-approved drugs, including off-label prescriptions. Results: Among the samples received, 85.3% of samples passed quality control requirements for SNV/Indels and amplifications. Majority of the tumor types were categorized under colorectal cancer (20.3%), NSCLC (18.7%), followed by breast cancer (13.6%). Of the samples successfully sequenced, actionable targets were identified in 76.2% of patients, with Tier I variants [such as EGFR exon19del (6), EGFR exon20insertion (1), ERBB2 amp (5), KRAS G12C (3), KRAS G12D (1), KRAS G12V(1), KRAS G12F (1) KRAS G13D (1), PIK3CA H1047R (1), MET exon 14 skipping (1) and NRAS Q61H (1)) being identified in 20 patients. When stratified across tumor types, actionability rates were found to differ, with 100.0%, 83.3% and 81.8%, of tested tissues samples yielding results informing treatment selection or resistance mutations for breast, colorectal and NSCLC respectively. Based on APEX-tissue testing, the median number of actionable genes identified was 2 (IQR: 0 – 3) while the mean time from sampling to report was 4.7 days. Conclusions: This study shows the clinical utility and feasibility of targeted panel testing in cancer types of breast, colorectal and NSCLC. With fast turnaround time of 4 working days, this ensures timely access to treatment for patients.
Impact of COVID-19 on the management of ureteric stones in the UK: The COVID Stones study
Authors: M.H.V. Byrne, F. Georgiades, C.E. Lovegrove, T. Klatte, K. Saeb-Parsy, R. Kumar, A. Light, R. Josephine, C. Dominic, S. Kathiravelupillai, S. Howles, G.D. Stewart, B. Turney, O. Wiseman
Journal: European Urology (2022)
Anlotinib plus letrozole in patients with platinum-resistant recurrent ovarian cancer: A prospective, single-arm, open-label, phase II study.
Authors: Xipeng Wang, Jiarui Li, Ping Zhang, Xuhong Fang, Yizhi Wang, Huizhen Sun
Journal: Journal of Clinical Oncology (2022)

e17545 Background: Studies have suggested that estrogen regulates the malignant transformation of ovarian surface epithelial cells, stimulates the growth and migration of cancer cells. and promotes the VEGF expression in epithelial ovarian cancer. Anlotinib is a novel multi-target tyrosine kinase inhibitor, inhibiting tumor angiogenesis and proliferative signaling. In this study, we evaluate the activity of anlotinib combined with letrozole in patients with estrogen receptor positive, platinum-resistant recurrent ovarian carcinoma (NCT04720807). Methods: Patients who have previously received two or more chemotherapy treatments, with histopathologically confirmed high-grade serous ovarian cancer (including salpingo carcinoma and peritoneal carcinoma), estrogen receptor (ER) positive and ECOG 0-2 were considered eligible for enrollment. Anlotinib was taken orally (10mg mg qd, d1-14, 21 days per cycle), and letrozole was taken orally (2.5mg qd, d1-21, 21 days per cycle). The treatment was continued until disease progression, death, or intolerant toxicity. The primary endpoint was objective response rate (ORR) and the secondary endpoints included disease control rate (DCR), duration of remission (DOR) progression free survival (PFS), overall survival (OS) and safety. Results: Between September 2020 and November 2021, 13 patients with a median age of 62 years (range:53-72), FIGO histopathological stage IC (23.1%), IIIC (53.8%) and IV (23.1%) were enrolled. Twelve of these patients have been evaluated for efficacy. In the efficacy-evaluable population (n=12), the therapeutic evaluation showed that 2 and 7 patients achieved partial response and Stable disease respectively, yielding the ORR of 16.7% (2/12, 95% CI: 3.3 to 54.3). The DCR was 75% (9/12, 95% CI: 39.3 to 93.3). The median PFS was 6.25 months (95% CI: 2.3m to not reached) and the median OS was not reached. The most common adverse events (AEs) were grade 1 or 2, which included laryngitis (69.2%), hypertension (53.8%), stomatitis (38.5%), diarrhea (30.8%), hand-foot syndrome (23.1%), and hyperuricemia (23.1%). The grade 3 AEs were hypertension (38.5%), diarrhea (7.7%) and hyperuricemia (7.7%). No higher AEs or treatment-related death were observed. Conclusions: Conclusions Anlotinib plus letrozole showed a promising efficacy with a favorable toxicity profile for patients with platinum-resistant recurrent ovarian cancer. The trial is ongoing and more data will be provided in the future. Clinical trial information: NCT04720807.
Correction: A novel tumor suppressor protein encoded by circular AKT3 RNA inhibits glioblastoma tumorigenicity by competing with active phosphoinositide-dependent Kinase-1
Authors: Xin Xia, Xixi Li, Fanying Li, Xujia Wu, Maolei Zhang, Huangkai Zhou, Nunu Huang, Xuesong Yang, Feizhe Xiao, Dawei Liu, Lixuan Yang, Nu Zhang
Journal: Molecular Cancer (2022)
Multiple suspicious PI-RADS lesions prior to mpMRI ultrasound fusion biopsy: Is it sufficient to target exclusively the index lesion?
Authors: P. Rachubinski, J.H. Witt, J. Zinke, B. Fangmeyer, T. Spieker, N. Liakos, M. Vetterlein, L. Budäus, M. Kachanov, S-R. Leyh-Bannurah
Journal: European Urology (2022)
Phase 2 study of first-line pembrolizumab in elderly patients with non-small cell lung cancer expressing high PD-L1.
Authors: Kosuke Hamai, Takeshi Masuda, Kazunori Fujitaka, Tomoko Suzuki, Naoko Matsumoto, Mirai Matsumura, Shoko Isoyama, Sayaka Ueno, Mineyo Mito, Kakuhiro Yamaguchi, Shinjiro Sakamoto, Reo Kawano, Ken Masuda, Ryohei Nishino, Nobuhisa Ishikawa, Masahiro Yamasaki, Noboru Hattori
Journal: Journal of Clinical Oncology (2022)

e21156 Background: Pembrolizumab is the recommended first-line therapy for patients with advanced non-small cell lung cancer (NSCLC) and a programmed death ligand-1 (PD-L1) tumor proportion score (TPS) of ≥50% without driver mutations. However, its efficacy and safety for patients ≥75 years has not been prospectively investigated; this was the aim of this study. Methods: This multi-center and open-label single-arm phase II study was conducted at 12 institutions. Chemotherapy-naïve patients with advanced NSCLC and a PD-L1 TPS of ≥50% without EGFR mutations or translocation of the ALK received pembrolizumab (200 mg) every 3 weeks. The primary endpoint was progression-free survival (PFS) with a threshold of 4.3 months. The secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), safety. Quality of life (QOL) was assessed using EORTC QLQ-C30 and EORTC QLQ-LC13. The patients completed the questionnaires immediately after providing informed consent, and also before the third, sixth, twelfth, eighteenth, and twenty-fourth treatment cycles. Results: Twenty-six patients were enrolled between October 2017 and March 2020. The median PFS was 9.6 (95% confidence interval [CI], 2.1–20.6) months. The lower limit of the 95% CI did not exceed the target. The median OS was 21.6 (95% CI, 15.1–not reached) months.The ORR and DCR were 41.7% (24.5–61.2) and 70.8% (50.8–85.1), respectively. The proportion of patients with Grade ≥3 treatment-related adverse events was 15.4%. The Score of Global Health Status/QOL, symptom scales and/or items, and functioning scales of EORTC QLQ-C30 and EORTC QLQ-LC13 did not change significantly during the treatment. Conclusions: This study showed pembrolizumab was tolerable treatment for the elderly patients. Although the primary endpoint, the median PFS (9.6 months) was slightly shorter than that (10.3 months) of the previous phase III study (KEYNOTE-024 study), the median PFS, did not achieve the expected value. Clinical trial information: UMIN000040474.
First-in-human phase I study of a ROR1-targeting bispecific T-cell engager (NVG-111) shows evidence of efficacy in patients with relapsed/refractory CLL and MCL.
Authors: Parag Jasani, William Townsend, Samir Asher, Sarrah Tayabali, David Tucker, Sarah Cook, Toby Batten, David Granger, Mittal Shah, Kieran O'Donovan, Amit C. Nathwani
Journal: Journal of Clinical Oncology (2022)

7535 Background: NVG-111 is a first in class, humanized, tandem scFv ROR1xCD3 bispecific T cell engager that mediates potent killing of ROR1 + tumours by engaging an epitope on the Frizzled domain of ROR1 and redirecting T cell activity via the CD3 binder. Methods: This phase I/II study is evaluating NVG-111 in patients with relapsed/refractory (R/R) CLL and MCL who have received ≥2 prior systemic therapies and have achieved a stable, or partial response to the last line of therapy. NVG-111 was delivered as continuous intravenous (cIV) infusion over 21 days per cycle, with each patient typically receiving 3 cycles of treatment. The first 3 single patient cohorts were subjected to accelerated dose titration (ADT) over a range of 0.3-30µg/day. Dose-escalation steps in the subsequent, multi-patient, cohorts were determined using a continuous reassessment method with overdose control. The primary endpoints are safety and determination of MTD/RP2D. Secondary objectives are pharmacokinetics, pharmacodynamics, immunogenicity and anti-tumor activity, assessed by multicolor flow cytometry to quantitate minimal residual disease (MRD4). Results: As of January 2022, six patients (all males, median age 60 years) had been enrolled to the study; three into each of the ADT cohorts and the remaining into a 30 µg/day flat dosing cohort. Five patients had CLL, and one had MCL, with all subjects remaining on ibrutinib whilst receiving NVG-111. The most common adverse events were Grade 1 lethargy, headaches, nausea, vomiting and thrombocytopenia. All 3 patients exposed to a flat dose of NVG-111 at 30µg/day suffered Grade 1 cytokine release syndrome (CRS) during week 1 of cycle 1. This did not require tocilizumab or dose interruption except in one patient who developed transient, grade 3 immune effector cell–associated neurotoxicity syndrome-like symptoms (ICANS). CRS or ICANS was not observed in subsequent cycles of treatment at this dose level. Response was observed in all 5 evaluable patients who had completed efficacy assessment after 3 cycles of NVG-111. Amongst these, 2 patients had undetectable MRD in the blood with one being MRD negative in the bone marrow. Dose escalation is ongoing, including exploration of step-up dosing. Conclusions: Early data with NVG-111 shows promising efficacy with a predictable and manageable safety profile. Clinical trial information: NCT04763083.
A first-in-human phase 1 study of the next-generation RET inhibitor, LOXO-260, in RET inhibitor refractory patients with RET-altered cancers (trial in progress).
Authors: Nathan A. Pennell, Lori J. Wirth, Justin F. Gainor, Julia K Rotow, Melissa Lynne Johnson, Todd Michael Bauer, Matthias Kroiss, Vineeth Sukrithan, Hyunseok Kang, Francis P. Worden, Christine M. Bestvina, Julien Hadoux, Philippe Alexandre Cassier, Antoine Italiano, Juergen Wolf, Marcia S. Brose, Emin Avsar, Michael D. Axelson, Vivek Subbiah, Alexander E. Drilon
Journal: Journal of Clinical Oncology (2022)

TPS8595 Background: RET fusions are found in 1-2% of lung adenocarcinomas and 10-20% of papillary thyroid carcinomas. Activating RET mutations occur in 50-60% of medullary thyroid cancers (MTCs). Selpercatinib was the first selective RET inhibitor approved by the FDA and is indicated for patients (pts) with RET fusion-positive NSCLC and thyroid cancer, and RET mutant MTC. Despite marked and durable activity, acquired resistance can eventually develop through a variety of mechanisms. These include acquisition of RET G810X mutations at the solvent front of the ATP pocket. LOXO-260 is a highly potent and selective inhibitor of RET designed to have activity against both solvent front and gatekeeper mutations, expressed alone or together, while maintaining potency against RET fusions or mutations (Kolakowski GR. et al. 2021 Cancer Research 81 (13 Suppl) 1464). Methods: LOXO-NGR-21001 is a global, open-label, first-in-human phase 1 study of LOXO-260 in pts with RET fusion-positive advanced solid tumors and RET mutant MTC who received a prior selective RET inhibitor. Phase 1a dose escalation will utilize a modified i3+3 design, allowing for pt backfill to previously cleared dose levels. Phase 1b dose expansion will evaluate LOXO-260 in specific expansion cohorts: RET fusion-positive NSCLC or thyroid cancers and RET mutant MTC. The primary objectives in dose escalation are to determine the MTD/RP2D and safety of LOXO-260. Key secondary objectives include characterization of PK and preliminary antitumor activity of LOXO-260 per RECIST v1.1. The primary objective of dose expansion is to assess the antitumor activity of LOXO-260 based on investigator-assessed overall response rate (ORR). Key secondary objectives are to characterize the PK and antitumor activity of LOXO-260 based on progression-free survival (PFS), time to response (TTR), and duration of response (DOR). Eligible pts must have received a prior selective RET inhibitor, have a documented RET fusion or RET mutation and a diagnosis of locally advanced, unresectable and/or metastatic cancer per disease-specific criteria, and must have progressed or be intolerant to standard therapies or must have refused such a therapy. Pts must be ≥18 years old and have an ECOG PS of 0-2. Key exclusion criteria include presence of serious cardiac conditions, interstitial lung disease, symptomatic CNS metastases, or carcinomatous meningitis. Clinical trial information: NCT05241834.
The Lung ART adjuvant radiotherapy phase 3 randomized trial: Impact of quality of resection in stage IIIAN2 patients.
Authors: Pascal Alexandre Thomas, John G. Edwards, Ramón Rami-Porta, Paul Van Schil, Olaf Mercier, Jean Philippe Le Rochais, Pierre-Emmanuel Falcoz, Jean-Pierre Meunier, Eleni Gkika, Hireche Kheira, Oliver Riesterer, Maria Rosa Ghigna, Aurelie Bardet, Cecile Le Pechoux
Journal: Journal of Clinical Oncology (2022)

8522 Background: Lung ART is an international phase 3 trial whose main objective was to evaluate the impact of post-operative conformal radiotherapy (PORT) on disease-free survival (DFS) in patients with completely resected pathologically proven N2 non-small cell lung cancer (NSCLC), with or without neo- or adjuvant chemotherapy. Previously communicated results showed no impact of PORT on DFS. However, as quality of surgical resection and extent of lymph node dissection were expected to be critically important in the interpretation of results, surgical and pathological reports were centrally reviewed by a surgical committee. Methods: A surgical advisory committee composed of 4 expert thoracic surgeons reviewed anonymized surgical and pathological reports of all included patients. Pre-defined classification rules were defined using published guidelines from the International Association for the Study of Lung Cancer and the European Society of Thoracic Surgeons. Tumor resection was defined as complete (no residual tumor and adequate lymph node assessment), uncertain (highest mediastinal nodal station involved, incomplete nodal exploration, involved N2 removed in fragments) or incomplete (presence of residual tumor). Nodal exploration was classified as sampling, selective dissection or extensive dissection. Results: 501 patients were included in the Lung ART trial. Before surgical committee review intervention, all patients except 2 had complete resection. 496 patients’ reports were analyzed by the surgical advisory committee. The basic characteristics are specified in the following table: Conclusions: Monitoring of the quality of nodal exploration and of resection should be implemented in randomized studies evaluating peri-operative strategies in NSCLC in order to provide reliable and generalizable results. Clinical trial information: NCT00410683. [Table: see text]
Focal treatment of prostate cancer with High-Intensity Focused Ultrasound (HIFU): Oncological, functional and morbidity outcomes of a prospective and unicentric series
Authors: A.D. Partezani, P.P. Kayano, G.C. Mariotti, R.G. Garcia, R.H. Baroni, G.C. Lemos, A. Carneiro
Journal: European Urology (2022)